The emergence of in vivo resistance of Plasmodium falciparum malaria to standard antimalarial drugs is a major and growing threat to public health in Africa, Asia, and Latin America. Chloroquine treatment is now rarely effective. The usual replacement, Fansidar, is already losing efficacy. Compliance with quinine can only be achieved for 3 days because of intolerance, and 3 days does not result in cure. Artesunate, also usually given for 3 days, is again not curative. Pregnant women and young children bear the brunt of this disease, and constitute a particularly difficult treatment problem because the drugs commonly added to the above standard agents to augment efficacy-such as doxycycline/tetracycline or mefloquine-are contraindicated for these populations. Azithromycin is an agent that can be safely administered to all the above clinical populations, and the single-agent efficacy of azithromycin in the clinic is comparable to that of doxycycline /tetracycline.The overall aims of this project are to determine if combinations of azithromycin with the above standard agents provide satisfactory efficacy and tolerance including in pregnant women and children and if so, to formally develop such combinations for use in the US and worldwide. B. Specific Milestones and their associated hypotheses MILESTONE 1: test the hypothesis that in phase II "proof of concept"/dose-ranging clinical trials, One or more of the combinations of azithromycin with quinine, fansidar, chloroquine, or artesunate will be effective (90% cure) and well-tolerated for the treatment of uncomplicated P falciparum disease in relatively non-immune populations and also in semi-immune pregnant women. MILESTONE 2: test the hypothesis that in phase II/III clinical trials, the efficacious azithromycin combinations identified in milestone 1 are as safe and well tolerated. MILESTONE 3: test the hypothesis that in phase III pivotal trials including pregnant women and children, the efficacious azithromycin combinations identified in milestones 1 and 2 are safe and effective (95% cure) for drug-resistant malaria. MILESTONE 4: file a supplemental New Drug Application to the United States Food and Drug Administration for the use of azithromycin drug combinations for the treatment of P falciparum malaria, including in pregnant women and children.